Abstract 2854: LncRNA UCA1 as a potential therapeutic target for drug resistance in colorectal cancer
Authors: Kyle D. Doxtater, Manish K. Tripathi
Journal: Cancer Research (2023)

Abstract Cancer metastasis is one of the deadliest aspects of the disease, with about 90% of all cancer-related deaths due to its development at different sites within the body. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the United States, with 40-50% of all patients developing metastasis at some point during their fight with the disease. With the approval of Regorafenib for treating metastatic colorectal cancer, steps have been taken to combat metastasis in colorectal cancer. A vital aspect of the development of metastasis is the development of resistance to first-line chemotherapy. Regorafenib is an oral small-molecule multiple kinase inhibitor. It is indicated worldwide for patients with metastatic colorectal cancer (mCRC), Regorafenib has already begun to show resistance in CRC. Understanding the mechanisms behind Regorafenib resistance in CRC is vital. Studies have demonstrated the expression of Long-non-coding RNA (LncRNA) to be linked to cancer metastasis and drug resistance. LncRNA UCA1 has been shown in other cancers to lead to resistance to different drugs like cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib, and EGFR-TKIs. In our lab, we have found the LncRNA UCA1 to be overexpressed in CRC patient tissues, with increasing expression across stages I-III, compared to normal tissue. High UCA1 expression has decreased survival among colorectal cancer patients, per the TCGA patient cohort analysis. Furthermore, we found that high UCA1 expression in colorectal cancer cell lines leads to high IC50 values for Regorafenib. Lentiviral transduce stable overexpression (SW480), and knockdown (SW620) cell lines were developed for UCA1-regorafenib drug resistance mechanistic studies. Increased expression of UCA1 led to increased expression of crucial drug resistance genes (MDR1, ABCB1, and FOXM1) and increased IC50 compared to the control vector. In contrast, the knockdown of UCA1 led to decreased expression of resistance markers and IC50 in SW620 cells. A 3D spheroid model was utilized to assay regorafenib sensitivity to the UCA1 overexpressed and knockdown cell lines. High UCA1 expression leads to the formation of a higher number of 3D spheroid bodies and size when compared to vector. Furthermore, when treating the spheroid with IC50 concentration, UCA1 overexpressing spheroids showed higher vitality and increased size compared to the vector control. We have also analyzed the signaling pathways modulated by UCA1 in CRC cell lines, which may be involved in enhancing the regorafenib resistance. This supports the notion that UCA1 is critical in enhancing the resistance to regorafenib in CRC by activating drug resistance pathways. For the first time, this study demonstrates that UCA1 provides drug resistance to regorafenib in CRC, facilitating the progression of CRC metastasis. Citation Format: Kyle D. Doxtater, Manish K. Tripathi. LncRNA UCA1 as a potential therapeutic target for drug resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2854.